KR20040053239A - Compounds and Method for the Treatment of Overactive Bladder - Google Patents

Abstract

NK2R binding compounds in accord with structural diagram I useful for the treatment or prevention of OAB or UI in mammals, particularly humans are disclosed: wherein in said compounds D, A, R<SUP>1</SUP>, R<SUP>3 </SUP>and R<SUP>4 </SUP>are as defined in the specification. Pharmaceutically-advantageous salts of the compounds, methods of use of the compounds, either alone or in combination with other pharmacological agents, and pharmaceutical compositions useful in practicing the methods of the invention are also disclosed.

Description

Compounds and Methods for the Treatment of Overactive Bladder {Compounds and Method for the Treatment of Overactive Bladder}

The term overactive bladder ("OAB") refers to symptoms including urinary incontinence, urgency and urinary frequency. Urinary incontinence (“UI”) is an involuntary loss of urine caused by the bladder losing urine retention due to urgency (urgency incontinence), or physical or mental stress (stress incontinence).

Normal bladder is filled at the physiological rate indicated by kidney function. The bladder can accommodate large amounts of urine due to the neurological inhibition system as well as the physical properties of the bladder. The mechanism of inhibition is believed to be associated with an inhibition of parasympathetic activity or an increase in sympathetic nervous tension that causes the detrusor to relax and fill the bladder. While the bladder is filling, the bladder neck and urethra are contracted to prevent leakage. Release or urination is characterized in that the bladder neck and urethra are relaxed by contraction of the detrusor muscle. When the bladder is empty, the detrusor muscles relax and the bladder neck and urethra contract, confining the bladder and maintaining a suppressed state.

It is estimated that 4-8% of the total population suffers from UI at any time, but in most countries only about 15% of such patients are diagnosed. Only about 70% of diagnosed patients receive medical treatment. Emergency urinary incontinence is more common in older people and 80% of women are women. Many urinary incontinence patients who do not receive medical treatment regularly use pads or other physical devices. The U.S. incontinence pad market was estimated at $ 1.5 billion in 1997.

In Western countries, the muscarinic antagonist oxybutin is prescribed for the treatment of OAB, and the second generation muscarinic M3 receptor antagonist, tolterodine, is also marketed for OAB. In Japan, prefiberin and flaboxate are prescribed. Estrogen and progesterone therapies have been studied and are believed to alleviate some urinary incontinence in some women. Other studies suggest that alpha-adrenergic agonists, beta-adrenergic receptor blockers, choline receptor blocking compounds and choline receptor stimulating drugs may be beneficial. However, conventional therapies are associated with side effects, including constipation, poor visual adaptation, dry eye (dry eyes), and "dry mouth" side effects, which some users are not well tolerated with these side effects. There is an increasing need for effective and acceptable medical treatments that are not met by therapies.

The present invention relates to compounds useful for the treatment and / or prevention of overactive bladder or urinary incontinence, methods of using the compounds and compositions for use in the methods.

It has now been found that certain compounds that bind neurokinin 2 receptor (“NK2R”) are useful for the treatment and prevention of overactive bladder (“OAB”) and urinary incontinence or urinary incontinence (“UI”).

In one aspect of the invention, it has been found that certain novel compounds that bind to the NK2R receptor are useful for the treatment and prevention of OABs and UIs. This compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Where

A is O or S;

D is CH or NH;

R ¹ is H or C (O) NHR ² ;

R ² is C _1-4 alkyl;

R ³ is H or C _1-4 alkyl;

R ⁴ residues are selected from halogen, C _1-4 alkyl, C _1-4 alkoxy or cyano,

Provided that the compound is (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-thio-piperidin-1-yl) piperidino] butyl] -N- Methylbenzamide, (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) -4-carboxyaminoethyl-piperidino ] Butyl] -N-methylbenzamide, or (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-thioperhydro-pyrimidin-1-yl) piperi Dino] butyl] -N-methylbenzamide.

In another aspect of the invention,

A is O or S;

D is CH or NH;

R ¹ is H or C (O) NHR ² ;

R ² is C _1-4 alkyl;

R ³ is H or C _1-4 alkyl;

The R ⁴ moiety has been found to be useful for the treatment and prophylaxis of OABs and UIs of compounds of formula (I) selected from halogen, C _1-4 alkyl, C _1-4 alkoxy or cyano, or a pharmaceutically acceptable salt thereof.

In a more particular aspect of the invention A compound selected from A is O, D is CH, R ¹ is H, R ³ is CH ₃ and R ⁴ is H or halo is useful for the treatment and prevention of OAB and UI Do.

Even more particularly, compounds of formula (I) in which A is O, R ¹ is CH ₃ and R ² is fluoro, have been found useful in the treatment and prevention of OABs and UIs.

Most particularly, compounds useful for the treatment and prevention of OABs and UIs are the compounds exemplified herein.

The compounds of the present invention possess the property of binding to NK2R and these specific compounds selectively inhibit the contraction of bladder tissue. Surprisingly, it has been found that certain compounds of formula I activate the contraction of bladder tissue induced by BANK. One such compound is a compound wherein A is S, D is NH, R ¹ is H, R ³ is CH ₃ and R ⁴ is H. Another of these compounds is a compound wherein A is O, D is C (O) NHC ₂ H ₅ , R ¹ is H, R ³ is CH ₃ , and R ⁴ is H.

In one aspect of the invention there is provided a method comprising treating or preventing OAB or UI with a compound of formula (I) in a subject, in particular a human, and more specifically, comprising treating a therapeutically effective amount of a compound of formula (I) do.

In a second aspect of the invention, there is provided a compound for treating and preventing OAB or UI in a mammal, and in particular a human.

In a third aspect of the invention there is provided a pharmaceutically acceptable salt of a compound of the invention and a composition containing said compound or a pharmaceutically acceptable salt thereof.

In a particular aspect of the invention there is provided a method comprising treating or preventing OAB or UI in a therapeutically effective amount of a compound of formula (I) that inhibits bladder contraction in a subject, particularly a human.

In another aspect of the invention, treating OAB or UI in a mammal and in particular human comprising treating a subject in need thereof with a combination of a therapeutically effective amount of a compound that binds NK2R and another therapeutic agent. And methods of prevention.

In another aspect of the invention, a therapeutically effective amount of an NK2R antagonist and an estrogen preparation and / or with or without supplementation of an alpha-adrenergic agonist, a beta-adrenergic receptor blocker, a choline receptor blocking compound or a choline receptor stimulating drug Provided are methods for treating and preventing OAB or UI in mammals and particularly humans, comprising treating a subject in need thereof by combining progesterone substances.

In another aspect of the invention, there is provided a pharmaceutical composition useful in practicing the methods of the invention, comprising a compound of formula (I) and a pharmaceutically acceptable excipient or diluent thereof.

In all aspects of the invention, pharmaceutically acceptable salts contemplated as being within the scope of the present invention include, for example, hydrochloride, sulfate, tosylate, mesylate, leadylate, besylate, phosphate, salicylate, Salts such as tartrate, lactate, citrate, benzoate, succinate, fumarate, acetate or maleate.

It is an object of the present invention to provide a method of treating OAB or UI comprising the use of a compound of formula (I).

Another object of the present invention is to provide a method comprising preventing OAB or UI using a compound of the present invention.

The method of the invention is generally applicable to mammals, in particular to humans.

Accordingly, it is an object of the present invention to provide a method comprising treating a human patient suffering from OAB or UI and therefore in need thereof with a therapeutically effective amount of a compound of the invention.

Another object of the present invention is to provide a compound of formula I useful for the treatment or prevention of OAB or UI.

It is another object of the present invention to provide pharmaceutically acceptable salts, compositions, mixtures and the like of the compounds useful for the treatment or prevention of OAB or UI.

It is a particular object of the present invention to provide a method of treating a human patient suffering from OAB or UI, comprising administering to the human patient an amount of a compound of formula (I) effective for the treatment of the OAB or UI.

Another specific object of the present invention is to provide such a method of using the compound of formula I in the form of a pharmaceutically acceptable salt.

The therapeutic agents of the methods of the invention may be administered in any physiologically acceptable manner, such as topical application, ingestion, inhalation, aeration or injection.

In the process of the invention, the compounds of the invention may be in the form of capsules, tablets, aqueous solutions, aqueous suspensions, non-aqueous suspensions, suppositories, aerosols or powders.

An object of the present invention is an overactive bladder ("OAB"), or urgency (urgency incontinence), or physical or mental stress (stress incontinence) generally and herein referred to symptoms including urinary incontinence, urgency and urinary frequency. Urinary incontinence (“UI”), which refers to involuntary urinary loss due to loss of urinary capacity of the bladder.

It is therefore an object of the present invention to provide a method for treating a human patient suffering from OAB or UI.

As contemplated herein, a particular object of the method of the invention for the treatment of OAB or UI is to administer a therapeutically effective amount of a compound of formula (I).

Another object of the present invention is to provide a compound of formula I useful for the treatment or prevention of OAB or UI.

It is another object of the present invention to provide pharmaceutically acceptable salts, compositions, mixtures and the like of the compounds useful for the treatment or prevention of OAB or UI.

A particular object of the present invention is to provide an effective amount of (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxoperhydropyrimidin-1-yl in the treatment of OAB or UI. A method of treating a human patient suffering from OAB or UI, comprising administering)) piperidino] butyl] -N-ethylbenzamide to a human patient.

Another specific object of the present invention is (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxoperhydropyrimidin-1-yl) piperidino] butyl] It is to provide the above method of using -N-ethylbenzamide in the form of a pharmaceutically acceptable salt thereof.

The therapeutic agents of the methods of the invention may be applied topically via any physiologically acceptable route, eg, in the skin, sublingual, or rectum; Intraperitoneal, extra-intestinal, intradermal or subcutaneous; Or as a solution or suspension in capsules, tablets or liquid form.

In general, pharmaceutical compositions of the invention may be formulated to be administrable by physiologically acceptable routes. In the methods of the invention, the compounds may be administered in the form of capsules, tablets, aqueous solutions, aqueous suspensions, non-aqueous suspensions, suppositories, aerosols or powders.

In certain methods of the invention, the compound may be administered in combination with one or more other therapeutic agents. Such therapeutic agents include estrogen preparations, progesterone, alpha-adrenergic agonists, beta-adrenergic receptor blockers, choline receptor blockers or choline receptor stimulants. However, it will be apparent to those skilled in the art that the compounds of the present invention may be administered in combination with any medically compatible therapeutic or prophylactic agent and / or medicament or combination thereof.

The present invention may include pharmaceutical compositions comprising one or more pharmaceutically acceptable excipients or diluents with a compound of the present invention.

The present invention may also include pharmaceutical compositions comprising agents such as estrogen preparations, progesterone, alpha-adrenergic agonists, beta-adrenergic receptor blockers, choline receptor blockers or choline receptor stimulants.

Pharmaceutical compositions within the scope of the present invention may have such forms as capsules, tablets, aqueous solutions, aqueous suspensions, non-aqueous suspensions, suppositories, aerosols and powders.

In other respects, the objects and advantages of the invention will be apparent to those of ordinary skill in the art having read this specification and the appended claims.

However, when the compounds of the present invention are used in the treatment of OAB, UI or related diseases, the compounds of the present invention or pharmaceutically acceptable salts thereof, such as chlorides, sulfates, tosylate, mesylate, lead silates As a suitable pharmaceutical composition comprising, besylate, phosphate, salicylate, tartrate, lactate, citrate, benzoate, succinate, acetate, maleate, or other salts and pharmaceutically acceptable diluents or carriers It should be appreciated that the compounds of the invention may be administered. Such salts are prepared by methods known to those skilled in the art. The form of the pharmaceutical composition is modified to suit the particular route of administration chosen. Such forms include, for example, tablets, capsules, solutions or suspensions for oral administration; Solutions or suspensions for topical administration; Suppositories for rectal administration; Sterile solutions or suspensions for administration by intravenous or intramuscular infusion or injection; Aerosol or spray solutions or suspensions for inhalation administration; Or a mixture of powder and pharmaceutically acceptable solid diluent, such as lactose, for administration by aeration.

For oral administration, tablets or capsules containing a therapeutically effective amount of a compound of the invention in the range of 0.1 mg to 250 mg (and typically 5 mg to 100 mg) can be suitably used. For inhalation administration, the compounds of the present invention can be administered to humans once a day or divided into two to four times, for example, in a daily dosage range of 5 mg to 100 mg. Similarly, for intravenous or intramuscular injection or infusion, sterile solutions or suspensions containing up to 10% by weight (and typically 0.05 to 5% by weight) of the compounds of the invention can be suitably used.

Dosages of the compounds of the invention need to be altered in accordance with principles well known in the art, taking into account the route of administration and the severity, size and age of the condition of the patient being treated. In general, the compounds of the present invention will be administered in the range of about 0.01 to about 25 mg / kg, and more particularly 0.1 to 5 mg / kg. It will generally be appreciated that equivalent amounts of N-oxides or pharmaceutically acceptable salts or quaternary ammonium salts of the compounds of the invention may be used.

Unless otherwise stated, herein

(i) the temperature is in units of degrees Celsius (“° C.”) and the operating temperature range was room temperature or room temperature, ie 18-25 ° C .;

(ii) the organic solution was dried over anhydrous MgSO ₄ ; Solvent was evaporated in a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) at a bath temperature of 60 ° C. or lower;

(iii) chromatography means flash chromatography; Reversed phase chromatography was performed using an octadecylsilane (“ODS”) coated support having a particle diameter of 32-74 μm, known as “PREP-40-ODS” (Art 731740- by Bodman Chemicals, Aston, PA). Flash chromatography on 100); Thin layer chromatography (“TLC”) was performed on silica gel plates;

(iv) In general, TLC was carried out after the reaction proceeded and the reaction time is for illustration only;

(v) melting point is an uncorrected value and “dec” refers to decomposition; Melting points are obtained for materials prepared as described; In some preparations polymorphisms may appear in the process of isolating materials having different melting points;

(vi) the final product had a satisfactory proton nuclear magnetic resonance (“NMR”) spectrum;

(vii) Yields are for illustration only, not necessarily those obtained during the reaction; The preparation was repeated when more material was required;

(viii) When NMR data are described, these data are in the form of delta values of the main characteristic protons, in parts per million (“ppm”) relative to the internal standard tetramethylsilane (“TMS”), and as a solvent, overprotons ( perdeuterio) value determined at 300 MHz using dimethyl sulfoxide ("DMSO-d6"); Common abbreviations for signal shapes were used; Coupling constant (J) is in units of k; Designated Ar refers to an aromatic proton;

(ix) chemical symbols have a conventional meaning; SI units and symbols were used;

(x) decompression was stated in pascal units (“kPa”) as absolute pressure; The elevated pressure is stated in bar as the gauge pressure;

(xi) solvent ratios are described in volume: volume (“v / v”) terms;

(xii) LC / MS was detected with a diode ray detector. The analysis was performed with a Zorbax 50 mm x 2.1 mm stable bond C8 assay column. Solvent A was 0.05% trifluoroacetic acid in water. Solvent B had 90% of acetonitrile, 9.95% of water and 0.05% of trifluoroacetic acid. The flow rate was 1.4 ml / min and the slope of solvent B 5%-solvent B 90% in 3 minutes. Retention time was in minutes. The ionization method used APCI, or chemical ionization under atmospheric pressure. In general, only ions pointing to parent ions were reported.

Chemical Example

Example 1: (S) -N- [2- (3,4-Dichloro-phenyl) -4- (2-oxo- [1,4 '] bipiperidinyl-1'-yl) -butyl] -2 -Fluoro-N-methyl-benzamide.

(S) -1 '-[3- (3,4-Dichloro-phenyl) -4-methylamino-butyl]-[1,4'] bipiperidinyl-2- in dichloromethane (7 mL) at 0 ° C. To the warm (0.3 g) solution was added pure 2-fluorobenzoyl chloride. After 45 minutes at room temperature, the solution was washed with aqueous sodium bicarbonate solution, dried and purified by chromatography, taking an oil, eluting with methanol: dichloromethane (gradient 3:97, 6:94). Concentration in high vacuum to viscous oil gave the title compound (0.3 g). MS: m / z = 534 (M + 1).

(S) -N- [2- (3,4-Dichloro-phenyl) -4- (2-oxo- [1,4 '] bipiperidinyl-1'-yl) -butyl] -2-fluoro- Maleate salt of N-methyl-benzamide.

(S) -N- [2- (3,4-Dichloro-phenyl) -4- (2-oxo- [1,4 '] bipiperidinyl-1'-yl) -butyl] -2- as free base Fluoro-N-methyl-benzamide (11.7 g) was placed in isopropanol (80 mL), mixed with a solution of maleic acid (2.54 g) in isopropanol (80 mL), and heated to just before reflux. The mixture was cooled and stirred at room temperature overnight. The resulting solid was filtered and dried in vacuo (crop 1, 10.2 g). Harvest 1 was placed in isopropanol (250 mL) and refluxed until solution, then stirred at room temperature overnight. The solid precipitate was filtered off and dried in high vacuum (crop 2, 7.1 g). The mother liquor was evaporated from harvest 1 and the residue was taken up in isopropanol (50 mL) and stirred overnight. The crystals formed were filtered and vacuum dried (crop 3, 1.7 g). Both Harvest 1 and Harvest 3 were highly hygroscopic. Harvest 1 and Harvest 3 were dissolved by heating in ethanol (80 mL) and stirred overnight at room temperature. The next day no clear crystal was seen. Diethyl ether was added to dilute to 500 ml total volume. After 15 minutes a solid began to appear. After 5 hours the solid was filtered off, washed with 50:50 diethyl ether: ethanol and dried at 65 ° C. in high vacuum (7.5 g). MS: m / z = 534 (M + 1). C 28 H 34 Cl 2 FN 3 O 2 1.0 C 4 H 4 O 4 0.1 H 2 O Analysis: Calcd: C, 58.92; H, 5.902; N, 6.44; Found: C, 58.35-58.54, H 5.51-5.47, N 6.38-6.41.

(S) -1 '-[3- (3,4-Dichloro-phenyl) -4-methylamino-butyl]-[1,4'] bipiperidinyl-2-one intermediate was prepared as follows:

1a. (S)-[2- (3,4-Dichloro-phenyl) -4-hydroxy-butyl] -methyl-carbamic acid tert-butyl ester.

Di-tert-butyl dicarbonate in dichloromethane (125 ml) to a solution of 3- (3,4-dichloro-phenyl) -4-methylamino-butan-1-ol (25.0 g) in dichloromethane (125 ml) The solution was added dropwise. After stirring for 3 hours, the reaction mixture was washed with dilute hydrochloric acid and dilute sodium bicarbonate solution and evaporated to dryness. The resulting oil was chromatographed by eluting with dichloromethane: ether (2: 1).

1b. (S)-[2- (3,4-Dichloro-phenyl) -4-oxo-butyl] -methyl-carbamic acid tert-butyl ester.

To a solution of oxalyl chloride (2.84 mL) in dichloromethane (70 mL) at −78 ° C. was added a solution of dimethylsulfoxide (4.6 mL) in dichloromethane (35 mL). The mixture was stirred at −78 ° C. for about 7 minutes before (S)-[2- (3,4-dichloro-phenyl) -4-hydroxy-butyl] -methyl-carbamic acid in dichloromethane (25 mL). tert-butyl ester (9.1 g) solution was added. The mixture was stirred at -78 ° C for 30 minutes before pure triethylamine (18.1 mL) was added. The mixture was then stirred at −78 ° C. for 30 minutes and at 0 ° C. for 45 minutes and warmed to room temperature. The solution was diluted with dichloromethane, washed with dilute hydrochloric acid and aqueous sodium bicarbonate solution and evaporated to dryness. MS: m / z = 346 (M + l). The product was used without further purification.

1c. (S)-[2- (3,4-Dichloro-phenyl) -4- (2-oxo- [1,4 '] bipiperidinyl-1'-yl) -butyl] -methyl-carbamic acid tert-butyl ester.

To acetic acid (1.49 ml) was added to a solution of [1,4 '] bipiperidinyl-2-one (4.5 g) in methanol (100 ml). The solution was stirred for a few minutes before (S)-[2- (3,4-dichloro-phenyl) -4-oxo-butyl] -methyl-carbamic acid tert-butyl ester (26 mmol) in methanol (25 mL). Was added. After continuing stirring for 20 minutes, sodium cyanide borohydride (1.64 g) in methanol (5 mL) was added. The mixture was stirred for 2 days, then diluted with aqueous sodium bicarbonate solution and concentrated. It was then partitioned between a layer of water and dichloromethane. The aqueous layer was washed with dichloromethane, the organic phases were combined, dried and purified by flash chromatography taking off viscous oil and eluting with methanol: dichloromethane (5:95). This material formed white foam (9.4 g) during the vacuum drying process. MS: m / z = 512 (M + 1).

1d. (S) -1 '-[3- (3,4-Dichloro-phenyl) -4-methylamino-butyl]-[1,4'] bipiperidinyl-2-one.

Trifluoroacetic acid (13.1 ml) was dissolved in (S)-[2- (3,4-dichloro-phenyl) -4- (2-oxo- [1,4 '] bipiperidinyl- in dichloromethane (300 ml). 1'-yl) -butyl] -methyl-carbamic acid tert-butyl ester (8.73 g) solution was added. After stirring for 30 minutes, further trifluoroacetic acid (13.1 mL) was added. After 1.5 hours the reaction was diluted with aqueous sodium hydroxide solution and the layers separated. The organic layer was washed with water, dried and a viscous oil was taken but not further purified. MS: m / z = 412 (M + l).

Example 2: (S) -N- [2- (3,4-Dichlorophenyl) -4- [4- (2-thio-piperidin-1-yl) piperidino] butyl] -N-methyl Benzamide.

A solution of (S) -N- [2- (3,4-dichlorophenyl) -4-oxobutyl] -N-methylbenzamide (0.50 g) in methanol (2 mL) was dissolved in methanol (6 mL) [1, 4 '] bipiperidinyl-2-thione (0.34 g) and acetic acid (0.10 mL) were added to the solution. After 5 minutes, sodium cyanide borohydride (0.108 g) in methanol (2 mL) was added in one portion. After stirring overnight, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution, stirred for 30 minutes, and extracted with dichloromethane (3 x 50 mL). The organic extracts were dried, evaporated and purified by chromatography using dichloromethane: methanol (gradient 98: 2, 95: 5) as eluent. The resulting material was dissolved in dichloromethane, precipitated by the formation of a hydrochloride salt with etheric hydrogen chloride, evaporated and placed in high vacuum overnight to afford the title compound (0.490 g) as a white solid. MS: m / z = 532 (M &lt; + &gt;).

[1,4 '] bipiperidinyl-2-thione intermediate was prepared as follows:

2a. 4- (5-Chloro-pentanoylamino) -piperidine-1-carboxylic acid benzyl ester.

4-amino-piperidine-1-carboxylic acid benzyl ester (12.0 g) in dichloromethane (100 mL) was added to pyridine (7.2 mL). After the solution was cooled to 0 ° C., 5-chlorovaleryl chloride (7.3 g) was added dropwise to the reaction. The reaction was warmed to room temperature. After 5 hours, the reaction was diluted with dichloromethane and washed with water (1 ×), saturated copper sulfate aqueous solution (2 ×), and water (1 ×). The organic extract was evaporated to dryness. The resulting solid was suspended in ether, filtered and then placed in high vacuum to afford the title compound (15.6 g) as a white solid. R _f = 0.60 in ethyl acetate.

2b. 2-oxo- [1,4 '] bipiperidinyl-1'-carboxylic acid benzyl ester.

4- (5-Chloro-pentanoylamino) -piperidine-1-carboxylic acid benzyl ester (15.6 g) was added to a suspension of sodium hydride (2.12 g) in tetrahydrofuran (175 mL). After stirring overnight, the reaction was quenched with water and then tetrahydrofuran was removed under reduced pressure. The aqueous solution was diluted with water and extracted with methylene chloride (4 x 50 mL). The organic extract was evaporated to dryness to afford the title compound (15 g). R _f = 0.30 in ethyl acetate. MS: m / z = 317 (M + H).

2c. 2-thioxo- [1,4 '] bipiperidinyl-1'-carboxylic acid benzyl ester.

2-oxo- [1,4 '] bipiperidinyl-1'-carboxylic acid benzyl ester (3.1 g) in tetrahydrofuran (10 mL) was added to Lawesson's Reagent in tetrahydrofuran (40 mL). 1.98 g) was added to the suspension. After 20 minutes the reaction was concentrated and the resulting gum was chromatographed using methylene chloride: ether (gradient 10: 1, 5: 1) as eluent. The title compound (2.9 g) was obtained as a white foam. R _f = 0.42 in methylene chloride: ether (10: 1). MS: m / z = 333 (M + H).

2d. [1,4 '] bipiperidinyl-2-thione.

Anisole (2.5 mL) was added to a solution of 2-thioxo- [1,4 ′] bipiperidinyl-1′-carboxylic acid benzyl ester (2.4 g) in methylene chloride (40 mL) at 0 ° C. and then Fluorosulfonic acid (3.4 mL) was added. After 30 minutes, solid potassium carbonate was added followed by sodium sulfate and methanol. The solid was filtered off and the filtrate was concentrated. The residue was dissolved in methanol and neutralized by passing through a column of Amberlyst A-21 (weakly basic) resin. The filtrate was collected, concentrated and purified by chromatography using methylene chloride: methanol (gradient 95: 5, 90:10) as eluent. The title compound (0.93 g) was obtained as a white solid. MS: m / z = 199 (M + H).

Example 3: (S) -N- [2- (3,4-Dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methyl -3-fluorobenzamide.

3-fluorobenzoyl chloride (0.088 mL) was added (S) -1 '-[3- (3,4-dichloro-phenyl) -4-methylamino-butyl]-[1,4 in dichloromethane (78 mL). '] Reacted with bipiperidinyl-2-one (0.30 g) overnight. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic extract was evaporated to dryness and purified by chromatography using dichloromethane: methanol (gradient 97: 3, 94: 6) as eluent to afford the title compound (0.28 g). R _f = 0.36 in methylene chloride: methanol (95: 5). MS: m / z = 534 (M &lt; + &gt;). The product was dissolved in methanol (2 mL) and citric acid was added. The solution was concentrated and the residue triturated with ether. The product (0.093 g) was obtained as a white foam.

(S) -1 '-[3- (3,4-Dichloro-phenyl) -4-methylamino-butyl]-[1,4'] bipiperidinyl-2-one intermediate as described in Example 1 Prepared.

Example 4: (S) -N- [2- (3,4-Dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methyl -4-fluorobenzamide.

4-fluorobenzoyl chloride (0.093 mL) was added (S) -1 '-[3- (3,4-dichloro-phenyl) -4-methylamino-butyl]-[1,4 in dichloromethane (8 mL). Reaction with bipiperidinyl-2-one (0.325 g) overnight. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic extract was evaporated to dryness and purified by chromatography using dichloromethane: methanol (gradient 97: 3, 94: 6) as eluent to afford the title compound (0.33 g). R _f = 0.41 in methylene chloride: methanol (95: 5). The product was dissolved in methanol (2 mL) and citric acid was added. The solution was concentrated and the residue triturated with ether. The product (0.11 g) was obtained as a white foam.

(S) -1 '-[3- (3,4-Dichloro-phenyl) -4-methylamino-butyl]-[1,4'] bipiperidinyl-2-one intermediate as described in Example 1 Prepared.

Example 5: (S) -N- [2- (3,4-Dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methyl Benzamide.

(S) -N- [2- (3,4-dichlorophenyl) -4-oxobutyl] -N-methylbenzamide (0.78 g) in methanol (3 mL) was dissolved in methanol (8 mL) [1,4 '] Bipiperidinyl-2-one (0.34 g) and acetic acid (0.15 mL) were added to the solution. After 10 minutes, sodium cyanide borohydride (0.17 g) in methanol (4 mL) was added in one portion. After stirring overnight, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution, stirred for 30 minutes, and extracted with dichloromethane (4 x 50 mL). The organic extract was evaporated to dryness and purified by chromatography using dichloromethane: methanol (gradient 95: 5, 90:10) as eluent to afford the title compound (0.95 g). MS: m / z = 516 (M &lt; + &gt;). The product was dissolved in methanol (2 mL) and citric acid was added. The solution was concentrated and the residue triturated with ether. The product (1.2 g) was obtained as a white foam.

[1,4 '] bipiperidinyl-2-one intermediates were prepared as follows.

5a. [1,4 '] bipiperidinyl-2-one.

2-oxo- [1,4 '] bipiperidinyl-1'-carboxylic acid benzyl ester (2.5 g) and Perlman catalyst (0.50 g) in ethanol (30 mL) were stirred under hydrogen (1 atm) It was. After 20 hours the reaction was filtered through celite and concentrated. The title compound (1.45 g) was obtained as a white solid. MS: m / z = 183 (M + H).

5b. (S) -N- [2- (3,4-Dichlorophenyl) -4-oxobutyl] -N-methylbenzamide.

To a solution of oxalyl chloride (4.5 mL) in dichloromethane (100 mL) at -78 ° C was added dimethylsulfoxide (7.4 mL) in dichloromethane (40 mL). After complete addition, the solution was further stirred at -78 ° C for 30 minutes. Then (S) -N- [2- (3,4-dichloro-phenyl) -4-hydroxy-butyl] -N-methyl-benzamide in dichloromethane (35 mL) and dimethylsulfoxide (7 mL). (14.6 g) solution was added dropwise. The solution was stirred at -78 ° C for 1 hour. Triethylamine (29 mL) was added dropwise to the reaction, after 20 minutes the ice bath was removed and the solution was stirred at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane (200 mL) and washed with dilute aqueous hydrochloric acid solution (150 mL), water (150 mL) and aqueous sodium bicarbonate solution (150 mL). The separated organic layer was evaporated to dryness and then dissolved in ether. The white precipitate formed was filtered and dried to give the title compound (9.1 g). R _f = 0.41 in methylene chloride: methanol (95: 5).

Example 6: (S) -N- [2- (3,4-Dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) -4-carboxyaminoethyl-piperidino ] Butyl] -N-methylbenzamide.

1-benzyloxycarbonyl-4-carboxy-4- (2-oxopiperidino) piperidine (1.45 g), ethylamine hydrochloride (0.32 g), 4- (dimethylamino in dichloromethane (20 mL) ) -Pyridine (0.59 g), triethylamine (0.67 mL), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.92 g) solution were stirred overnight. The reaction mixture was diluted with dichloromethane and then washed with 1.0 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water. The separated organic layer was evaporated to dryness to afford the title compound (1.37 g) as a white solid which did not need to be purified. NMR: 7.35 (m, 5), 6.71 (m, 1), 5.12 (s, 2), 3.56 (m, 4), 3.28 (m, 4), 2.43 (m, 2), 2.27 (m, 2) , 2.20 (m, 2), 1.76 (m, 4), 1.11 (t, 3, J = 7.2).

The therapeutic action of the compounds of the invention for treating OAB or UI by binding to the NK2 receptor has been shown by conducting appropriately designed in vitro and in vivo tests.

In vitro binding assay

Preparation of Membrane from MEL Cells Transfected with Cloned Human NK1 or NK2 Receptors

Cloning of human lung NK1 and NK2 receptors is described by Hopkins, et al., Biochem. Biophys. Res. Commun. 180: 1110-1117 (1991), and Graham, et al., Biochem. Biophys. Res. Commun. 177: 8-16 (1991). Heterologous expression and scale-up growth of MEL cells transfected with human tachykinin receptors are described in Aharony, et al., Mol. Pharmacol. 45: 9-19, 1994, as described for the NK2 receptor.

Membranes were prepared from recombinant MEL cells expressing NK1 or NK2 receptors as described above in Hopkins, et al. (1991). In summary, cells were composed of 50 mM Tris-HCl (pH 7.4), 5 mM KCl, 120 mM NaCl, 10 mM EDTA at 4 ° C. and various protease inhibitors (1 mM phenylmethylsulfonylfluoride; 0.1 mg / ml Homogenized in buffer containing soy trypsin inhibitor and 1 mM iodoacetamide (Brinkman PT-20 Polytron, set 3, rupture once for 15 seconds on ice). The homogenate was centrifuged at 1200 x g for 45 minutes at 4 ° C to remove cell debris. The supernatant was centrifuged at 48,000 × g, 45 minutes at 4 ° C. The pellet was resuspended in a 30-volume ice-cold 50 mM Tris-HCl (pH 7.4) buffer with a free-teflon autogeniser.

Receptor binding assays:

See Aharony, et al., Mol. Pharmacol. 45: 9-19, 1994, Aharony, et al., Neuropeptides 23: 121-130 (1992) and Aharony, et al., J. Pharmacol. Exp. Ther. 259: 146-155 (1991), using [ ³ H] NKA in MEL cells expressing the cloned NK2 receptor or [ ³ H] SP in MEL cells expressing the cloned NK1 receptor Ligand binding assays were performed using. In summary, incubation in assay buffer containing membrane, test compound and [ ³ H] ligand (1.0-1.5 nM). In the competition experiments, mixtures containing various concentrations of the competitive agent (agonist, antagonist or vehicle) (0.315 mL), with or without unlabeled 1 μM uniform ligand (NKA or SP), to define nonspecific binding Was incubated at 25 ° C. for 30 minutes. The reaction was initiated by adding a membrane (0.1 to 0.15 mg protein / final concentration) and run in duplicate. Saturation experiments and dynamic experiments were performed in triplicate. The ligand and free ligand bound to the receptor were diluted with 1 ml of wash buffer (20 mM Tris-HCl, pH 7.5) and immediately isolated by vacuum filtration with a total volume of 10 ml of wash buffer (Watt pre-soaked with 0.1% polyethyleneimine). Brandel cell harvester with Whatman GF / B filter (using Brandel Cell Harvester MB-48R).

The ability of the compounds disclosed herein to inhibit the binding of the [ ³ H] ligand is shown in the results disclosed in Table 1.

In vivo analysis:

BANK-Induced Bladder Contraction in Anesthetized Guinea Pigs:

Female guinea pigs (300-450 g) were anesthetized by intramuscular administration of a ketamine / xylazine mixture (3/10 mg / kg each). A catheter was inserted into the jugular vein and a syringe for administering the compound in the appropriate place at the end of the catheter was connected. The abdominal centerline was then incised to expose the bladder, approximately 2 cm above the ureter's bladder was tied with a 4-0 silk suture, and the upper part of the bundle was cut to drain the kidneys. Intubation was passed through the adjacent urethra and bladder diaphragm to the bladder lumen. The bladder was emptied by hand, 0.3 ml of brine was injected and a conduit was attached to a Gould p23 ID pressure transducer to record changes in bladder pressure. After surgical sampling, the animals were allowed to equilibrate for approximately 15 minutes to stabilize. Fifteen minutes after administration of thiorphan (10 mg / kg iv), exposure to agonists inhibited neutral endopeptidase 3.4.24.11.

After allowing the reaction to decay for a 15 minute equilibration period, the test compound (0.2-5 mmol / kg, PEG 400 5% -saline vehicle) was administered intravenously. After an additional 15 minutes of equilibration, an equivalent amount of BANK was repeated. Preliminary studies were conducted to demonstrate the equivalence of bladder contractile responses to multiple doses of BANK. The effect was calculated as the percent difference between the response to BANK in the presence and absence of the test compound.

To demonstrate the effect of oral administration of test compounds, animals were administered test stomach (52 nmol / kg, PEG 400 5% -saline vehicle) 1 hour prior to BANK administration. BANK (3 nmol / kg) was then administered intravenously. The increase in bladder contraction that occurred in the presence or absence of test compounds was recorded on a Glass 7D biorecorder and expressed as percent inhibition of BANK-mediated effects. The time of action was studied by oral administration of test compounds (1.2 mmol / kg, PEG 400 5% -saline vehicle) at different times prior to BANK administration. The response was calculated as the percent difference between the response to BANK in the presence of the test compound and the sham-treated control. In all studies, each animal received a single dose of test compound. The experimental results show the percent change from the reference level as the standard error of the mean ± mean (S.E.M).

The ability of the compounds disclosed herein to inhibit bladder contraction induced by BANK is shown in the results disclosed in Table 1.

Example Compound Inhibition of BANK mediated GP bladder contraction (% inhibition mediated by orally administered 52 nM / kg) hNK2 (Ki is represented as log mole) hNK1 (Ki is represented as log mole) One 80 ± 6 8.84 7.04 2 42 ± 13 8.73 7.22 3 - - - 4 -28 ± 45 - - 5 - 8.48 6.37 6 -65 ± 58 9.70 84% inhibition at 10 μM

Compounds of the invention are specific for the NK2 receptor. As illustrated by the results shown in Table 1, the compounds described herein generally exhibit at least 100-fold selectivity for the human NK2 receptor relative to the human NK1 receptor.

Surprisingly, compounds with similar binding affinity to human NK2 receptors were found to have different effects when tested for the ability to inhibit bladder contraction induced by BANK. For example, as shown in Table 1, the exemplified compounds generally have about 9-log molar Ki when tested for their ability to inhibit tritium-NKA binding to cloned and expressed hNK2 receptors. However, it was found that the compound of Example 1 inhibits BANK induced bladder contraction by 80%, while unexpectedly, the compound of Example 4 inhibits BANK induced bladder contraction by 28%.

The compounds of the present invention showed no adverse effects in experimental animals that received multiple doses of the minimum effective dose.

Claims (19)

A compound of formula (I) or a pharmaceutically acceptable salt thereof <Formula I> Where A is O or S; D is CH or NH; R ¹ is H or C (O) NHR ² ; R ² is C _1-4 alkyl; R ³ is H or C _1-4 alkyl; R ⁴ residues are selected from halogen, C _1-4 alkyl, C _1-4 alkoxy or cyano, Provided that the compound is (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-thio-piperidin-1-yl) piperidino] butyl] -N- Methylbenzamide, (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) -4-carboxyaminoethyl-piperidino ] Butyl] -N-methylbenzamide, or (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-thioperhydro-pyrimidin-1-yl) piperi Dino] butyl] -N-methylbenzamide. The method of claim 1, A is O, D is CH, R ¹ is H, R ³ is CH ₃ , R ⁴ is selected from H or halo. The method of claim 1, A is O, R ¹ is CH ₃ , R ² is fluoro. The method of claim 1, (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methyl-2-fluor Robbenzamide; (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methyl-3-fluor Robbenzamide; (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methyl-4-fluor Robenzamide, and Selected from (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methylbenzamide Compound. The compound of claim 4, wherein (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N -Methyl-2-fluorobenzamide. A method of treating or preventing overactive bladder or incontinence in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject suffering from overactive bladder or incontinence. <Formula I> Where A is 0 or S; D is CH or NH; R ¹ is H or C (O) NHR ² ; R ² is C _1-4 alkyl; R ³ is selected from H or C _1-4 alkyl, R ⁴ residues are selected from halogen, C _1-4 alkyl, C _1-4 alkoxy or cyano. The method of claim 6, A is O, D is CH, R ¹ is H, R ³ is CH ₃ , R ⁴ comprises administering a compound selected from H or halo. The method of claim 6, A is O, R ¹ is CH ₃ , R ² comprises administering a compound that is fluoro. The method of claim 6, (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methyl-2-fluor Robbenzamide; (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-thio-piperidin-1-yl) piperidino] butyl] -N-methylbenzamide; (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methyl-3-fluor Robbenzamide; (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methyl-4-fluor Robbenzamide; (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methylbenzamide; (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) -4-carboxyaminoethyl-piperidino] butyl]- N-methylbenzamide, and In (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-thioperhydro-pyrimidin-1-yl) piperidino] butyl] -N-methylbenzamide A method comprising administering a compound of choice. The compound of claim 6, wherein (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N Administering -methyl-2-fluorobenzamide. The method of claim 6, wherein the subject is a human. The method of claim 6 wherein the pharmaceutically acceptable salt is chloride, sulfate, tosylate, mesylate, leadylate, besylate, phosphate, salicylate, tartrate, lactate, citrate, benzoate, succinate , Acetate or maleate. The method of claim 6 further comprising co-administering with one or more other therapeutic agents that are medically compatible. The method of claim 13, wherein said other therapeutic agent is selected from estrogen preparations, progesterone, alpha-adrenergic agonists, beta-adrenergic receptor blockers, choline receptor blocking compounds, or choline receptor stimulating drugs. The method of claim 6, wherein the compound or a pharmaceutically acceptable salt thereof is administered in a physiologically acceptable manner selected from topical application, ingestion, inhalation, aeration or injection. The method of claim 15, wherein said compound or pharmaceutically acceptable salt thereof is administered topically. The compound of claim 15, wherein the compound or a pharmaceutically acceptable salt thereof is in a daily dosage ranging from 5 mg to 100 mg in the form of a capsule, tablet, aqueous solution, aqueous suspension, non-aqueous suspension, suppository, aerosol or powder. A method comprising administering once a day or dividedly twice, three or four times. (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl) piperidino] butyl] -N-methyl-2-fluor A pharmaceutical composition for the treatment or prevention of overactive bladder or incontinence, comprising robbenzamide or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients or diluents. (S) -N- [2- (3,4-dichlorophenyl) -4- [4- (2-oxo-piperidin-1-yl for the manufacture of a medicament for the treatment or prophylaxis of overactive bladder or incontinence ) Piperidino] butyl] -N-methyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof.